Abstract

Purpose: Previous studies have shown that inhibitors of the serine/threonine kinase PLK1 potently induce cell death in human BCR/ABL+ leukemia cells both sensitive and resistant to imatinib mesylate (IM; Cancer Research 70:1513, 2010). Furthermore, HDACIs are known to potentiate tyrosine kinase lethality in such cells. The goal of the present studies was to determine whether PLK1 inhibitors (e.g. BI2536) and HDACIs interacted synergistically in BCR/ABL+ cells sensitive or resistant to imatinib mesylate in vitro and in vivo and if so, to identify the mechanism(s) underlying this interaction. Experimental

Design: K562 and LAMA84 cells, IM-resistant Adult-T315I and BV173/E255K cells, and primary CML cells were exposed to BI2536 with or without vorinostat (Merck) for various intervals. Effects on apoptosis and signaling pathways were determined by flow cytometry, western blotting, and gene transfection. K562 and BV173/E255K cells were used to test the in vivo efficacy of this drug regimen in animal models.

Conclusions: These findings suggest that concomitant PLK1 and HDAC inhibition is active against IM-sensitive or refractory CML cells both in vitro and in vivo, and that this strategy warrants further evaluation in the setting of BCR/ABL+ leukemias.